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Title: Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.
Authors: Lin SH,  Sampson JN,  Grünewald TGP,  Surdez D,  Reynaud S,  Mirabeau O,  Karlins E,  Rubio RA,  Zaidi S,  Grossetête-Lalami S,  Ballet S,  Lapouble E,  Laurence V,  Michon J,  Pierron G,  Kovar H,  Kontny U,  González-Neira A,  Alonso J,  Patino-Garcia A,  Corradini N,  Bérard PM,  Miller J,  Freedman ND,  Rothman N,  Carter BD,  Dagnall CL,  Burdett L,  Jones K,  Manning M,  Wyatt K,  Zhou W,  Yeager M,  Cox DG,  Hoover RN,  Khan J,  Armstrong GT,  Leisenring WM,  Bhatia S,  Robison LL,  Kulozik AE,  Kriebel J,  Meitinger T,  Metzler M,  Krumbholz M,  Hartmann W,  Strauch K,  Kirchner T,  Dirksen U,  Mirabello L,  Tucker MA,  Tirode F,  Morton LM,  Chanock SJ,  Delattre O,  Machiela MJ
Journal: PLoS One
Date: 2020
PubMed ID: 32881892
PMC ID: PMC7470401
Abstract: BACKGROUND: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. METHODS: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). RESULTS: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8). CONCLUSIONS: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. IMPACT: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.